Dopamine (DA) neurons in the ventral tegmental area (VTA) project to the nucleus accumbens (NAc) and the prefrontal cortex to make up the mesolimbic DA system. This system is heavily implicated in addiction to drugs of abuse. Previous findings from our laboratory show that glutamate synapses onto VTA DA neurons undergo synaptic plasticity following cocaine exposure. Importantly, numerous studies implicate that glutamatergic synaptic plasticity is a cellular mechanism that leads to learning. We propose that addiction results from usurpation of normal learning mechanisms by drugs of abuse. We will test this hypothesis using an animal behavioral model of addiction, cocaine self-administration, to examine the effects of instrumental learning on synaptic plasticity in the mesolimbic system. In particular, synaptic function will be compared in animals self-administering cocaine to those that received cocaine through a yoked design: these animals experience the pharmacological effects of cocaine without any instrumental learning. As synaptic changes in the VTA would undoubtedly affect DA release in the NAc, an important target region of the VTA, we will use also fast-scan cyclic voltammetry (FCV) to examine the dynamics of synaptic DA release in the NAcc. Thus, this application will study synaptic changes in both the VTA and the NAc, in the context of a relevant animal model of cocaine addiction. Our findings will extend the current understanding of the addiction process to aid in the development of treatments for individuals suffering from cocaine addiction. [unreadable] [unreadable] [unreadable]